The cellular responses controlled by the secreted Wnt proteins are essential to almost all aspects of embryogenesis. In developed tissue, genetic and molecular alterations that give rise to misactivation of these signaling processes frequently drive cancerous cell growth. We have identified two distinct chemical strategies to disable Wnt-mediated signaling from screening a large synthetic chemical library in cultured cells. Whereas one compound class targets an acyltransferase essential for the production of Wnt molecules, another class promotes the destruction of a linchpin transcriptional co- activator. The cell growth inhibitory effect of disabling Wnt-mediated signaling in certain cancerous contexts is well established. Yet, the ability of chemically based strategies to achieve similar effects is largely untested. The studies in this proposal will interrogate Wnt-mediated signaling at the molecular, cellular, and organismal level using new chemical biology-based tools, and establish a framework for the deployment of Wnt inhibitors in cancerous contexts. In particular, we focus on lung cancer given the dependence of this disease on both targets of our compound portfolio. These studies should facilitate a transition from front-line anti-cancer agents that are generally toxic to rapidly diving cells to those that are tailored to the underlying genetics of individual cancers.

Public Health Relevance

Deviant activation of cellular responses controlled by the Wnt family of secreted molecules is common in cancerous cells. Our study will delineate novel mechanisms of Wnt-mediated signaling using new chemically based strategies, and evaluate the effectiveness of two novel classes of small molecules that target Wnt-mediated signal transduction for inhibiting tumor initiation and progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA168761-02
Application #
8634750
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Arya, Suresh
Project Start
2013-04-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$450,087
Indirect Cost
$167,013
Name
University of Texas Sw Medical Center Dallas
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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You, Lin; Zhang, Chengwei; Yarravarapu, Nageswari et al. (2016) Development of a triazole class of highly potent Porcn inhibitors. Bioorg Med Chem Lett 26:5891-5895
Tuladhar, Rubina; Yarravarapu, Nageswari; Lum, Lawrence (2016) Monitoring Wnt Protein Acylation Using an In Vitro Cyclo-Addition Reaction. Methods Mol Biol 1481:11-6
Lum, L; Chen, C (2015) Chemical Disruption of Wnt-dependent Cell Fate Decision-making Mechanisms in Cancer and Regenerative Medicine. Curr Med Chem 22:4091-103
Kulak, Ozlem; Chen, Hua; Holohan, Brody et al. (2015) Disruption of Wnt/β-Catenin Signaling and Telomeric Shortening Are Inextricable Consequences of Tankyrase Inhibition in Human Cells. Mol Cell Biol 35:2425-35
Kulak, Ozlem; Yamaguchi, Kiyoshi; Lum, Lawrence (2015) Identification of therapeutic small-molecule leads in cultured cells using multiplexed pathway reporter readouts. Methods Mol Biol 1263:3-14
Tuladhar, Rubina; Lum, Lawrence (2015) Fatty acyl donor selectivity in membrane bound O-acyltransferases and communal cell fate decision-making. Biochem Soc Trans 43:235-9
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Fan, Chih-wei; Tuladhar, Rubina; Lum, Lawrence (2013) Signaling: Making a leaner Hedgehog. Nat Chem Biol 9:217-8